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Rationale: Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease causing paralysis and death from respiratory failure. Strategies to preserve and/or restore respiratory function are critical for successful treatment. Although breathing capacity is maintained until late in disease progression in rodent models of familial ALS (SOD1G93A rats and mice), reduced numbers of phrenic motor neurons and decreased phrenic nerve activity are observed. Decreased phrenic motor output suggests imminent respiratory failure.
Objectives: To preserve or restore phrenic nerve activity in SOD1G93A rats at disease end stage.
Methods: SOD1G93A rats were injected with human neural progenitor cells (hNPCs) bracketing the phrenic motor nucleus before disease onset, or exposed to acute intermittent hypoxia (AIH) at disease end stage.
Measurements and Main Results: The capacity to generate phrenic motor output in anesthetized rats at disease end stage was: (1) transiently restored by a single presentation of AIH; and (2) preserved ipsilateral to hNPC transplants made before disease onset. hNPC transplants improved ipsilateral phrenic motor neuron survival.
Conclusions: AIH-induced respiratory plasticity and stem cell therapy have complementary translational potential to treat breathing deficits in patients with ALS.
Although ventilatory failure is the most common cause of death in amyotrophic lateral sclerosis (ALS), no treatments are available to preserve or restore breathing capacity.
We present two novel approaches: (1) stem cell transplants to preserve breathing capacity and (2) intermittent hypoxia to restore breathing capacity. These treatments slow phrenic motor neuron cell death and increase activity in spared phrenic motor neurons, respectively.
Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease causing paralysis and death from respiratory failure (1, 2). Decreased inspiratory muscle strength (3–5) suggests inspiratory motor neuron degeneration, although extreme inspiratory maneuvers are necessary to demonstrate functional deficits until late in ALS disease progression. Ultimately, inspiratory motor neuron death exceeds the capacity for compensation, causing ventilatory failure and ventilator dependence or death (3, 6, 7). It is essential to develop new strategies that preserve respiratory function in patients with ALS.
Although the pathogenesis of ALS is under active debate (8–10), one major hypothesis is that it is not cell autonomous, and that astrocytes near motor neurons contribute significantly to disease progression (11, 12). Thus, providing healthy astrocytes near motor neurons may slow motor neuron death. Others hypothesize that diminished trophic factor support contributes to motor neuron degeneration in ALS (13, 14). Because many trophic factors are neuroprotective to motor neurons, delivery of relevant growth/trophic factors may prolong motor neuron survival (13). However, clinical trials using growth factors have experienced limited success (15–19), possibly due to inadequate delivery and/or choice of growth factors.
The primary goal of the present study was to harness strategies that preserve and/or restore the capacity to increase inspiratory activity in the major nerve innervating the diaphragm (phrenic nerve) in a rat model of ALS (SOD1G93A mutant rats) (1, 20). First, we induced a form of brain-derived neurotrophic factor (BDNF)–dependent phrenic motor plasticity known as phrenic long-term facilitation (pLTF) with acute intermittent hypoxia (AIH) (21, 22). AIH represents a novel means of inducing new BDNF synthesis and increasing phrenic motor output (21). Second, human neural progenitor cells (hNPCs) were implanted near phrenic motor neurons to replenish functional astrocytes (23). Finally, hNPCs modified to secrete glial cell line–derived neurotrophic factor (GDNF; previously shown to slow lumbar motor neuron degeneration in SOD1G93A rats [24]) were implanted near phrenic motor neurons. Functional outcomes were assessed by measuring motor neuron survival and phrenic motor output at disease end stage. Some results of these studies have been previously reported in abstracts (25–27).
Male SOD1G93A Sprague Dawley rats were bred to wild-type females (Taconic Laboratories, Germantown, NY) (23, 24). All experiments were performed on adult males at end stage (~150–180 d); end stage was defined as a 20% decrease from peak body mass.
Rats from three generations were studied, with focus on (1) breathing capacity measurements (Figure 1), (2) studies of AIH-induced pLTF (Figure 2), and (3) stem cell transplantation (Figures 3–6). Electrophysiology and then histochemistry were performed in all groups. Age-matched, wild-type littermates served as controls. All animal procedures were approved by the Institutional Animal Care and Use Committee at the University of Wisconsin (Madison, WI), and were in agreement with standards of the Guide for the Care and Use of Laboratory Animals (National Research Council, Washington, DC). The University of Wisconsin is accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International (AAALAC), and is covered by National Institutes of Health (NIH) Assurance (A3368-01).
To assess breathing capacity, unanesthetized rats (n = 4 for SOD1G93A and wild-type) were placed in a whole-body plethysmograph (Buxco Electronics, Wilmington, NC) as described previously (28). Tidal volume (milliliters) and minute pulmonary ventilation (milliliters per minute) were measured during baseline and maximal chemoreceptor stimulation (inspired gas: 7% CO2, 10.5% O2).
At end stage, mutant and wild-type rats were anesthetized for neurophysiological assessment of phrenic nerve activity (29). To assess integrated phrenic activity during baseline and maximal chemoreceptor activation, stable baseline conditions were established (>30 min) and the rat was then exposed to 10– to 20–mm Hg increases in end-tidal CO2 until maximal nerve activity was achieved (arterial Pco2, ~90 mm Hg). Inspired gases were changed at 8-minute intervals; arterial blood gases were measured during baseline and 6 minutes after inspired gas changes. Wild-type (n = 18) and SOD1G93A rats (n = 13) were exposed to AIH. During AIH protocols, blood gases were determined as previously described (29). For rats with hNPC transplants, blood gases were tested during baseline, 20 and 40 mm Hg above baseline CO2, and 40 mm Hg above baseline CO2 with hypoxia.
After neurophysiology experiments, rats were perfused and their tissues prepared for immunohistochemistry (28). After ventilatory studies, cervical (C3–C5) and thoracic (T5) spinal cord and brainstem regions containing hypoglossal motor neurons were sectioned (28). After AIH and hNPC studies, cervical sections (C3–C6) were made (24, 28). In AIH studies, primary antibodies were for neuronal nuclei (NeuN, mouse monoclonal, diluted 1:500; Chemicon, Billerica, MA), and the secondary antibody was goat anti-mouse green fluorescent Alexa 488 (diluted 1:500; Molecular Probes, Eugene, OR). In hNPC studies, primary antibodies included human-specific nuclear antigen (hNuc), choline acetyltransferase (ChAT), and anti-human cytoplasmic protein marker STEM121 (SC121, mouse monoclonal, diluted 1:2,000; StemCells Inc., Newark, CA) followed by secondary antibodies conjugated to Alexa Fluor 594 or Alexa Fluor 488 (diluted 1:500; Molecular Probes). Human GDNF immunohistochemistry was described previously (24).
Using manual morphometric analyses, phrenic motor neurons were counted in the C4 ventral horn. Phrenic motor neurons were defined by a cluster of large mediolateral neurons in the C4 ventral horn (30, 31). After plethysmography and AIH studies, six C4 sections (40 μm thick) were counted. Counting criteria included a clearly defined nucleus with intact chromatin (nonpyknotic) and a cytoplasmic membrane in large cell bodies characteristic of motor neurons. The number of phrenic motor neurons in the C4 segment was extrapolated from the six sections (length of C4 phrenic motor nucleus, ~2,000 μm; 40-μm sections). After hNPC studies, 3–11 sections (35 μm thick), relatively evenly spaced along the C4 segment (2,000 μm), were visualized (24) with the ×40 objective of a fluorescence M2 imager microscope (distance between counting frames, 100 μm; frame size, 100 × 100 μm; optical dissector height, 23 μm; guard zone thickness, 2.5 μm). Only complete motor neurons with an identifiable cell body and visible 4′,6-diamidino-2-phenylindole (DAPI)–counterstained nucleus were counted. The total phrenic motor neuron number at C4 was extrapolated from the average phrenic motor neuron count per section (2,000-μm C4 segment; 35-μm sections).
Methods to grow hNPCs from fetal cortex have been described (32, 33), and conform to NIH, University of Washington, and University of Wisconsin guidelines for collection of fetal tissues. Institutional review board (IRB) approval was obtained for all studies. GDNF-secreting hNPCs (hNPC-GDNF) or unaltered hNPC neurospheres were prepared for transplantation as described (23, 24, 34). To produce dead cells, hNPCs were incubated (30 min) at –80°C and thawed; live/dead cell counts confirmed 100% cell death. For transplantation, presymptomatic (110–120 d) SOD1G93A rats were anesthetized, positioned in a stereotaxic frame, and laminectomy and durotomy from C3 to C6 (24) were performed. Cell injections were made as described previously (24) at C3 and C6, and then the rats were allowed to recover from surgery; the rats were carefully monitored for 2 to 3 days, and then returned to the animal facility until they reached end stage.
SOD1G93A rats included hNPCs (n = 15), hNPC-GDNF (n = 12), dead hNPCs (hNPC-dead; n = 9), and nonsurgical controls (No Tx; n = 11). Nonsurgical, wild-type littermates (n = 11) were also included. Rats received cyclosporine (intraperitoneal, 10 mg/kg; Novartis) daily to prevent human cell rejection, beginning 1 day before surgery and continuing until sacrifice.
Plethysmography data were analyzed via Buxco software (28). Integrated phrenic nerve burst amplitudes were averaged over 1 minute during baseline; 15, 30, and 60 minutes post-AIH or baseline; and maximal output. Phrenic nerve burst amplitude is reported as the voltage of the integrated signal (see Figure E1 for validation of measurement), as the ipsilateral-to-contralateral ratio or as a percentage change from baseline. Statistical comparisons between treatment groups for plethysmography, maximal phrenic activity, and AIH studies were done by two-way analysis of variance (ANOVA) with repeated measures design. One-way ANOVA was used to compare (1) integrated phrenic activity at baseline or 60 minutes post-AIH, (2) maximal phrenic activity in wild-type versus SOD1G93A rats, and (3) histology data. After ANOVAs, individual comparisons were made using Student-Newman-Keuls or Fisher least significant difference (LSD) post hoc tests (SigmaPlot version 12.0; Systat Software Inc., San Jose, CA). For integrated phrenic nerve burst amplitudes (voltage) and ipsilateral-to-contralateral voltage ratios in hNPC studies, a split plot analysis with repeated measures was done (SAS or Statistical Analysis Software version 9.1.3; SAS Institute Inc.). All differences between groups were considered significant if P < 0.05; all values are expressed as means ± 1 SEM. Multiple linear regression analyses were performed between baseline or maximal phrenic activity with phrenic motor neuron counts.
Combined hypercapnia and hypoxia was used to elicit a standardized level of increased ventilatory drive, enabling assessment of the capacity to increase inspiratory volume (28). Measurements were made when SOD1G93A rats reached end stage (20% decrease from peak body mass) and in age-matched, wild-type littermates. No significant differences were observed between SOD1G93A (n = 4) and wild-type rats (n = 4) in tidal volume (milliliters) or minute ventilation (milliliters per minute) when breathing air or during chemoreceptor stimulation (Figures 1A and B). Thus, the capacity to generate inspiratory volume is preserved in end-stage SOD1G93A rats at a time when limb paralysis is already severe.
Cervical (C4; phrenic), thoracic (T5; intercostal), and hypoglossal motor neuron counts in SOD1G93A and wild-type rats at end stage revealed major losses of phrenic (large, pyramidal-shaped cells in the medioventral gray matter at C4 [30]) and T5 motor neurons in SOD1G93A rats (Figures 1C–1E). Motor neuron degeneration was not observed in the hypoglossal motor nucleus, which maintains upper airway patency (Figure 1E). Because the capacity to increase inspiratory volume is preserved despite major inspiratory motor neuron loss, unknown mechanisms of compensatory plasticity preserve breathing capacity at end stage in SOD1G93A rats.
Integrated phrenic nerve activity (28) was assessed in anesthetized SOD1G93A and wild-type rats during baseline (normocapnia, hyperoxia) and maximal chemoreceptor stimulation (arterial Pco2 ≥ 90 mm Hg) at end stage. Phrenic burst amplitude was significantly decreased during maximal chemoreceptor stimulation (Figure 1F). Collectively, in all groups of SOD1G93A rats presented here (Figures 2 and and3),3), phrenic burst amplitude was significantly decreased during both baseline and maximal chemoreceptor stimulation. Deficits in phrenic nerve activity suggest that motor neuron cell death will eventually exceed the capacity for compensation, resulting in ventilatory failure as shown in a murine ALS model (35).
Phrenic long-term facilitation (pLTF) is expressed as a prolonged increase in phrenic motor output after AIH (three 5-min hypoxic episodes; PaO2, ~35 to 45 mm Hg; 5-min intervals) in wild-type rats (21, 22) (Figures 2A and 2B). In end-stage SOD1G93A rats, pLTF was significantly greater in SOD1G93A versus wild-type rats 60 minutes post-AIH (Figures 2C–2E). AIH increased phrenic activity in end-stage SOD1G93A rats (Figure 2F) to levels equal to baseline levels in wild-type rats (in volts; Figure 2F), demonstrating that AIH restored phrenic motor output to normal levels in this model.
To establish whether hNPCs (with or without GDNF release) preserve phrenic motor output in SOD1G93A rats, bilateral phrenic nerve activity was recorded under baseline conditions and graded chemoreceptor stimulation at end stage (Figure 3). In SOD1G93A rats without treatment or receiving dead hNPCs, integrated phrenic activity was significantly decreased at baseline (Figure 4A) and during maximal chemoreceptor stimulation (Figure 4B); thus dead cells have no beneficial effects. In contrast, maximal integrated phrenic activity ipsilateral to hNPC transplants was significantly greater than in SOD1G93A rats without treatment or receiving dead hNPCs, and was no longer significantly different from wild-type rats (Figure 4B). Both hNPCs and hNPC-GDNF transplants significantly increased the ipsilateral-to-contralateral ratio of integrated phrenic bursts (Figures 4C and 4D) at baseline. However, only hNPCs significantly increased this ratio during chemoreceptor stimulation (Figures 4C and 4D). A ratio of about 2 with hNPC transplants (baseline and maximal) indicates full preservation (or restoration) of phrenic activity on the side of hNPC implantation because the normal decrement at end stage is about 50%. Thus, hNPCs preserved phrenic activity at wild-type levels, although GDNF secretion had no additional benefit.
At end stage, surviving phrenic motor neurons were surrounded by hNPCs labeled with a human-specific antibody for human nuclear protein (Figures 5A–5C). When visualizing hNPCs with the human-specific antibody, they were differentiated into astroglial-like cells, with processes extending around motor neurons (Figures 5D and and5E).5E). Double labeling with astrocyte (glial fibrillary acidic protein [GFAP]) and progenitor (nestin) markers revealed that most cells migrating from the transplant were not mature astrocytes but, rather, immature, nestin-positive cells as described previously (24). We did not see any neurons maturing from these grafts, as described previously (24). Increased GDNF immunoreactivity was detected surrounding GDNF-secreting hNPCs (Figure 5F).
Phrenic motor neurons were identified as large ChAT+ neurons in a cluster located in the mediolateral ventral horn at C4, as previously identified by retrograde tracer studies (30, 31). The number of phrenic motor neurons was significantly decreased in end-stage SOD1G93A rats (Figure 6A; also Figure 1). hNPC transplants significantly increased phrenic motor neuron counts (Figure 6A), indicating decreased cell death. hNPC-GDNF transplants had no significant effect, although there was an insignificant trend toward greater phrenic motor neuron survival (Figure 6A). Dead hNPCs exaggerated phrenic motor neuron loss (Figure 6A), suggesting unique effects of dead human cells, possibly due to inflammatory responses.
There were also reduced numbers of nonphrenic motor neurons in the C4 segment at end stage (Figure 6B). However, in contrast to phrenic motor neurons, ipsilateral counts of nonphrenic motor neurons were significantly increased by GDNF-secreting hNPCs, but not hNPCs alone. Thus, GDNF exerts beneficial effects on nonphrenic cervical motor neurons, similar to a previous study on lumbar motor neurons (24), but unlike the phrenic motor neurons studied here (Figure 6B).
Significant positive correlations were detected between integrated phrenic nerve activity and phrenic motor neuron counts ipsilateral to hNPC injections during baseline (slope = 0.32; R2 = 0.12; P < 0.05; Figure 6C) and chemoreceptor stimulation (slope = 0.98; R2 = 0.15; P < 0.05; Figure 6D). As expected, neither baseline nor chemoreceptor-stimulated phrenic activity correlated with contralateral motor neuron survival (P > 0.05). Although hNPCs may preserve the capacity to increase phrenic nerve activity via modest increases in phrenic motor neuron survival, this effect is not sufficient to account for all of the increase in phrenic motor output (Figures 3–5). Other possible mechanisms of improved function include improved motor neuron health or hNPC-induced motor plasticity.
Despite major inspiratory motor neuron loss, breathing capacity is preserved in end-stage SOD1G93A rats. This observation demonstrates that remarkable compensatory strategies preserve this critical homeostatic function during disease progression. However, there are signs of imminent respiratory failure, expressed as diminished capacity to generate phrenic nerve activity. Eventually, compensation will be inadequate, and progressive motor neuron death will cause overt ventilatory failure (3, 5–7, 35). It is essential to find new strategies that preserve and/or restore lost phrenic motor function before we can successfully treat patients with ALS.
Here, we demonstrate the potential of two novel strategies to treat respiratory insufficiency: (1) induction of phrenic motor plasticity with intermittent hypoxia, and (2) improving phrenic motor neuron survival and function via neural progenitor cell transplants. These strategies are complementary, and have considerable translational potential to treat breathing deficits in ALS.
Despite its importance to the survival of patients with ALS, little is known concerning the impact of disease progression on breathing capacity in animal models of ALS. In SOD1G93A rats, phrenic motor neuron degeneration, diminished compound diaphragm action potentials, phrenic nerve fiber loss, and diaphragm atrophy are reported at disease end stage (36). Despite this suggestive evidence of respiratory compromise, functional deficits in the ability to generate inspiratory volume were not assessed in their study (36). Further, the ability to generate inspiratory volume is maintained until late in disease progression in SOD1G93A mice, but tidal volume falls abruptly over the next 1–2 days (35); respiratory motor neuron degeneration was not reported in their study.
Spontaneous compensatory plasticity may delay ventilatory failure in patients with ALS, despite major respiratory motor neuron loss. Possible compensatory mechanisms include (1) central neural plasticity, amplifying respiratory motor output from surviving motor neurons; (2) motor end plate sprouting in surviving phrenic motor neurons, functionally increasing the size of diaphragm motor units; and/or (3) shifting inspiratory functions from the diaphragm to other inspiratory muscles. This last strategy is intrinsically limited because motor neuron death is also observed in other inspiratory motor pools. An understanding of spontaneous compensatory plasticity may have major health implications because it may guide the development of novel therapeutic interventions to slow or reverse breathing deficits in ALS.
Functional benefits may be achieved by inducing further plasticity, such as AIH-induced pLTF (22). This is the first report of pLTF in any ALS model. In fact, pLTF was enhanced in end-stage SOD1G93A rats, restoring most of the capacity to generate phrenic motor output. Thus, intermittent hypoxia may be an interesting and simple means of restoring lost breathing capacity in ALS, similar to its application after cervical spinal injury (28, 37). Mechanisms enhancing AIH-induced pLTF in end-stage SOD1G93A rats are not yet known.
Because BDNF is critical for AIH-induced pLTF (21), BDNF may be sufficient to preserve phrenic motor function in end-stage SOD1G93A rats. Because repetitive AIH restores respiratory and nonrespiratory motor function after cervical spinal injury (28), repetitive AIH may be a simple means of up-regulating endogenous growth/trophic factors to promote phrenic motor neuron survival and function (e.g., BDNF, vascular endothelial growth factor, and erythropoietin) (21, 38, 39). At present, no data are available concerning the hypothesis that repetitive AIH elicits neuroprotective responses in respiratory or nonrespiratory motor neurons.
To date, there has been limited success in administering BDNF in clinical trials (17–19). It is possible that BDNF delivery may cause TrkB down-regulation, or that TrkB may already be activated maximally. In contrast, both BDNF and TrkB are up-regulated by repetitive AIH (40), suggesting that AIH may represent a highly novel means of "delivering" BDNF without receptor down-regulation. On the other hand, truncated TrkB.T1 receptor deletion delays disease onset and muscle weakness in SOD1G93A mice, although disease end stage remained unchanged (41); this finding is consistent with at least some negative BDNF effects.
Another strategy to preserve or restore phrenic motor output during ALS is to provide healthy cells that effectively "repair" the environment surrounding phrenic motor neurons. We used human fetal neural progenitor cells that produce mainly astrocyte-like cells and protect motor neurons in the lumbar spinal cord of SOD1G93A rats, but only when expressing GDNF (23, 24). Here, we found that hNPCs improve phrenic motor neuron output and survival, without additional benefit from GDNF (Figures 3–5). Thus different motor neuron pools appear to be differentially responsive to GDNF and astrocyte replacement, possibly related to their location or function (42, 43). Indeed, considerable heterogeneity exists in spinal motor neuron properties (44–46).
Mechanisms whereby hNPCs protect phrenic motor neurons and restore phrenic activity are not known. Although hNPCs differentiate into astrocyte-like cells in the spinal cord (24), longer times are necessary to mature into fully functional GFAP-expressing astrocytes (47, 48). hNPC transplantation in the lumbar spinal cord does not reduce astrocytosis or activate microglia, suggesting that their beneficial effects arise via other mechanisms (24). Other mechanisms that could cause the effects observed here include (but are not limited to) the following: (1) wild-type hNPCs could increase glutamate uptake; (2) wild-type hNPCs could release beneficial growth/trophic factors other than GDNF; and/or (3) phrenic motor neurons may lack a GDNF response because the phrenic motor nucleus lacks GDNF receptors.
Because patients with ALS eventually develop ventilatory failure, new strategies to delay respiratory motor neuron death and enhance the functional capacity of spared motor neurons via induced respiratory plasticity are desirable. Here we demonstrate that mechanisms increasing function in surviving motor neurons (AIH-induced plasticity) or slowing phrenic motor neuron death (hNPCs) may be viable treatment strategies. AIH is noninvasive, simple to perform, and has minimal risk of adverse effects (currently used protocols are modest in number and severity of hypoxic episodes [22]). Indeed repetitive AIH has considerable potential in the treatment of both respiratory (22, 28) and nonrespiratory motor disorders/deficits (28, 49). Further, an ongoing clinical trial using neural stem cell transplants in patients with ALS is beginning to incorporate injections near respiratory motor pools (50, 51). Combinatorial strategies involving hNPC transplants and repetitive intermittent hypoxia represent viable (and complementary) strategies to preserve/restore functional deficits in ALS.
The authors thank Peter Crump for statistical advice, Kalen Nichols for help with blood gas analysis, and Antonio Punzo for technical support.
Supported by NIH NS057778 and the ALS Association. N.L.N. supported by NHLBI Training Grant HL007654 and the Francis Families Foundation. G.G. funded by Fonds de Recherche en Santé du Quebec (FRSQ). L.J.N. supported by NIH Training Grant RR023916.
Author Contributions: All authors contributed to the conception, design, or analysis of the study, and have approved submission of this manuscript.
This article has an online supplement, which is available from this issue's table of contents at www.atsjournals.org
Originally Published in Press as DOI: 10.1164/rccm.201206-1072OC on December 6, 2012
Author disclosures are available with the text of this article at www.atsjournals.org.
PubMed Central Canada is a service of the Canadian Institutes of Health Research (CIHR) working in partnership with the National Research Council's national science library in cooperation with the National Center for Biotechnology Information at the U.S. National Library of Medicine(NCBI/NLM). It includes content provided to the PubMed Central International archive by participating publishers.


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The Matrix Reloaded (Widescreen Edition) [DVD]
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In the second chapter of the Matrix trilogy, Zion falls under siege to the Machine Army. Only hours before 250,000 Sentinels destroy the last human enclave on Earth--and its growing resistance--Neo (Keanu Reeves) and Trinity (Carrie-Anne Moss) choose to return to the Matrix with Morpheus (Laurence Fishburne), unleashing their arsenal of extraordinary skills and weaponry against the forces of repression and exploitation.Now, at the confluence of love and truth, faith and knowledge, purpose and reason, Neo must follow the course he has chosen if he is to save humanity from the dark fate that haunts his dreams--The Matrix Reloaded.]]>
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When I first saw the film, well, I didn't like it too much. It seemed to be over-packed with CGI Fight scenes and a storyline that didn't really mean anything. While Zion is under attack, Neo, Trinity, and Morpheus must find the keymaster to unlock the doors to the mainframe and end the war, thus freeing Zion.
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We are introduced to two 'french' characters, programs, which exist simply to experience life. While they are among the long list of villians in this piece, they are also the key to the story. They describe the situation in as much in the film, seeing our heroes as mere puppets in a meaningless plot, which, in fact, they are.
While are main characters are engaged in a meaningless task, struggling to achieve goal after goal in a virtual world, events of the real world are dire, and, just perhaps, if more attention were paid to the real-world events, perhaps the situation would not be so dire.Read more ›
The core of the second movie is the discovery that the entire premise of the first was a lie. The Prophecy is just another layer of control. The machines created Zion, selected the One, and set him up to start the cycle, just to keep people pacified; the naturally rebellious would have an outlet for their energies that could never threaten the status quo at all. Zion and the human resistance are no more nor less than a machine-created pressure valve for the Matrix itself. That idea is brilliantly clever; breathtakingly so. If the movie had been made with that at its heart, with everything else there just to serve the story, you'd have a movie that excelled the first, and could stand alone. But that wasn't what happened. And the failure of that story means that the last movie failed too, because its own story was equally muddled and equally squandered, and that compounded the problems.Read more ›
It starts off with Neo dreaming of Trinity's death. This especially worries him now that the two of them are extra close. Things only get worse when it's realized that the machines threatening Zion are moving in closer and will threaten the city's survival if something isn't done in twelve hours (specifically if something isn't done by Neo, him being The One and all). You've probably heard that Agent Smith now has the ability to copy himself from anyone else in the Matrix. I won't tell you how (I hate spoilers as much as the next guy). I will say that it's an especially cool way to bring him back for the sequel, gining him much more power and presenting a seemingly unsurpassable conflict. There's an superbly done car chase thrown in near the end, plus a good look into the city of Zion and a lot of incredible secrets unveiled about the Matrix. I give it a missing star because there were just a few points in the plot I couldn't understand, but that is absolutely it.Read more ›
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Up and Running with Prelude CS6
Adobe Prelude, new in CS6, is a tool for ingesting and quickly organizing tapeless media for post-production. In this course, author Jeff Sengstack introduces the Prelude workflow, showing how to ingest raw footage, transcode media to various file formats, assemble assets, and tag clips with searchable metadata. The course also demonstrates creating rough-cut sequences, trimming and rearranging clips, and exporting projects to Premiere Pro and Final Cut Pro.
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- Jeff Sengstack
- [Voiceover] Hi, I'm Jeff Sengstack. Welcome to Up and Running with Prelude CS6. In this course I'm gonna show you all the various steps that you go through inside Prelude. That workflow starts by ingesting, this is where you go out and identify clips that you want to transfer over to another location. Or transcode, and when you transcode clips your clips show up here inside the Prelude Project panel. Then you want to work on those clips, you work on them by adding markers. Those markers might include comments like this or a Subclip. Once you marked things up, close Prelude and take those clips and open them up inside Premier Pro or Final Cut Pro and those markers will show up there.
But you probably want to make a rough cut, where you take a number of clips and lay them down in a particular order. And once the rough cut is done you can export the project, put all of its media, and then open up inside of Premier or Final Cut Pro. So those are the basic steps I'm gonna explain in this course, Up and Running with Prelude CS6.
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ART; Exhibit A (as in Art) in a Case for Conservation
Published: June 21, 1998
(Page 2 of 2)
The best-known, best-loved and probably the best artist of the school was a native Californian, Guy Rose, who spent eight years at Giverny, though he probably never painted with Monet. Traveling up and down California, he perfected the feathery brush strokes of early Impressionism, incorporating delicate purples, blues and pinks. Like Monet, he often did serial paintings of the same scene at different times of day. With six works in the show, he is its most represented artist. His ''Laguna Eucalyptus, 1916'' and ''Point Lobos, 1918'' are among the exhibition's highlights.
Another notable artist in the show is Granville Redmond, who could not hear or speak and who suffered bouts of depression. He preferred the moody, tonalist paintings seen in his dark yet intensely spiritual ''Nocturne,'' but he knew that wealthy patrons wanted his sunny trademark panoramas of poppy fields below snow-covered mountains, exemplified in the mural-like ''California Landscape With Flowers.''
The show also includes works by the Austrian-born Franz Bischoff, known for delicate floral paintings and vases as well as landscapes; the Hungarian-born Maurice Braun, who painted the burnt-sienna canyons of San Diego; John Gamble, a Santa Barbara resident who captured the intense purple of the lupines that covered the valleys, and Anna Hills, Joseph Kleitsch, Joseph Raphael, Arthur Rider, Elmer Wachtel and his wife, the watercolorist Marion Kavanagh Wachtel. (The exhibition also includes a smaller showing of California Impressionist paintings from the collections of Paul and Kathy Bagley and Thomas and Barbara Stiles, which closes on July 5.)
Six of the artists were National Academy members, and at least two paintings in the show -- Paul Dougherty's ''Twisted Ledge'' and Wendt's haunting ''There Is No Solitude'' -- were exhibited at the academy early this century. ''It's like a homecoming for these artists, though most people here have never heard of them,'' said David Dearinger, the academy's chief curator (the show's guest curator is William H. Gerdts). Mr. Dearinger said that a ''certain East Coast snobbism'' may have kept California Impressionism from gaining a popular foothold in the East.
Mrs. Smith agreed. ''Easterners don't think we can do anything out here in California,'' she said by telephone from her home, in San Juan Capistrano. ''But the East Coast doesn't have the light, or the geography.'' Still, she credited one group of Easterners, the 19th-century Hudson River School, with being the first environmental painters. ''They painted to protest the Industrial Revolution and destruction of the land,'' she said, ''just like the Californians after them.''
Mrs. Smith is a daughter of perhaps Orange County's most famous family (along with their friends, the Richard Nixons). In 1957 she succeeded her mother, Athalie Richardson Irvine Clarke, as a director of the Irvine Company, which was set up to manage and develop the family's sprawling livestock and produce ranch. For 25 years she clashed with other directors over the company's future and its plans to convert the ranch into a city. She pushed for responsible development of the ranch, insisting on a master plan that included preservation of natural areas. And she fought to donate 1,000 acres to build the University of California, Irvine.
In 1991, after a nine-year lawsuit, Mrs. Smith received $257 million for her interests in the company. She used some of that money to start her Impressionist collection and the Irvine Museum, which opened in January 1993; she also owns a gallery in Laguna Beach.
Her influence lingers. Last year, the Irvine Company and the Nature Conservancy joined to preserve 17,000 acres of endangered coastal sage scrub. ''Some of these paintings might well have been painted on that land,'' Mrs. Smith said. ''The artists would be very happy.''
Photos: CALIFORNIA DREAMING ''Point Lobos, 1918,'' by Guy Rose, a Californian who traveled up and down the state perfecting an Impressionist style. (Joan Irvine Smith Fine Art Inc.)(pg. 31); COASTAL GRANDEUR ''The Silent Summer Sea, 1915,'' by William Wendt, a German-born painter. (Joan Irvine Smith Fine Arts, Inc.)(pg. 33)


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Robyn Racicot's Profile
Helloooo, I'm Robyn. :D
Creep Allure is a one-man show run entirely by myself, born from a mixture of my love for all things creepy and cute, and from having far too much time on my hands.
I've had an unhealthy obsession with crafting for as long as I can remember, (which often lead me to trouble as a child. Sorry mom! I thought your expensive towels looked much nicer with buttons and glitter glued on..) but diy fashion and sewing quickly became my main focus. After much persuasion, and maybe a bit of nagging, from the people around me telling me I should sell my designs, I thus bring you Creep Allure. :D 100% Hand made and one-of-a-kind designs.
Facebook! http://www.facebook.com/pages/CreepAllure/163221660414019
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- Phelan, CA, United States
Creep Allure


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Ventnor will soon regain some of the sand its beaches lost to Hurricane Sandy - without most of its beach users having to move out of the way of the beach-rebuilding bulldozers.
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Gators silence the Bulldogs' barking with some chomping of thei...
There are 127 comments on the Orlando Sentinel story from Nov 1, 2008, titled Gators silence the Bulldogs' barking with some chomping of thei.... In it, Orlando Sentinel reports that:O nce again, there was an excessive celebration. Actually, there was an obsessive, expressive and impressive celebration.
Join the discussion below, or Read more at Orlando Sentinel.
#130 Nov 4, 2008
Hey guys!! Long time Gator fan in Indaina here. I must say,what a trouncing. I was also extremely disappointed that FSU lost as I felt if they could keep winning, and the Gators beat them, that would help us even more. But I sincerely feel as long as the Gators keep winning, they will make it into the National title game. I do think Texas Tech will get beat by either OSU or OU. We have the opportunity to take care of Alabama in the title game, if they don't get beat by LSU, which they shouldn't. I also think we will vault Texas in the standings in time. The only team I don't see getting beat is Penn State, but not because they are a great football team, rather, they play in the Big Ten, and we have all seen what happens to Big Ten teams in the title game. Just ask the Suckeyes. I will further say, being in Indiana, which is part of Big Ten Country, that people up here live and die Big Ten football, but they have no freakin concept of talent, strength, or speed. Also, in the SEC, there is a big game every week. I think this year the SEC is probably not as strong as last year, or even 2 years ago, however, there is still a big game every week and teams like Ole Miss, Kentucky, and Vandy could all beat Big Ten teams most times. I do agree, however, that there should be a playoff, something. I think several teams should at least get a shot on the field but this day will not come anytime soon. GO GATORS!!
#131 Nov 4, 2008
That is because many of the Gators get big bucks to go to the NFL and the Noles get to take their CPA degree and become their accountants. ummm who looks smarter?
Since: Oct 08
#132 Nov 5, 2008
I'm sure the tears will fall like rain after they play 'Bama.
#133 Nov 5, 2008
Please! Every body keeps saying that UF will fall every week since the season started. Yes they stumbled. Nobody has played better in the country since that loss. As the Gators move on(unlike the crying Bulldogs) their opponents fans keep saying that another team will take care of the business their team was unable to take care of. To that I say, BRING ON THE TIDE! We shall see what happens! Meanwhile, GO GATORS!! PS. When is the last time the Dawgs won a NC.........or a SEC champ.?
#136 Nov 5, 2008
Sounds like your speaking from experience.
#137 Nov 6, 2008
Chomp Chomp..........
#138 Nov 6, 2008
So I think we need a playoff system rather than the BCS list because this is nonsense..
Gators are without a doubt the most dominate team this season but still the people that make the BCS list don't consider them a top choice...
It doesn't make sense...
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Welcome, skip to the content.
The two mountains in this park provide excellent and diverse adventures for bushwalkers, campers, climbers, four-wheel drive enthusiasts, birdwatchers and nature lovers.Pine Mountain, one of Australia's largest monoliths, has a drier climate that supports many rare plants. Mount Burrowa, an area of higher rainfall, supports wet forest plants and is more heavily timbered.Choose one of the many walks ranging from an easy stroll to a three or four day trek which should challenge the serious hiker.Before you goConditions can change in parks for many reasons. For the latest information on changes to local conditions, please visit the relevant park page on the Parks Victoria website.Be bushfire ready in the great outdoors. Refer to the Bushfire Safety section on the Parks Victoria website for tips on how to stay safe.
The park is located 430 km from Melbourne, via the Hume Highway, Wodonga, Tallangatta and Cudgewa. Main access is from the Cudgewa-Tintaldra Road, which runs off Murray Valley Highway about 15 km west of Corryong.


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Screening for dysglycaemia in patients with coronary artery disease as reflected by fasting glucose, oral glucose tolerance test, and HbA1c: a report from EUROASPIRE IV, a survey from the European Society of Cardiology
2015) EUROPEAN HEART JOURNAL. 36(19). p.1171-U98 Mark(
Adverse lifestyle trends counter improvements in cardiovascular risk factor management in coronary patients
2015) JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY. 66(14). p.1634-1636 Mark(
- Does pharmacologic treatment in patients with established coronary artery disease and diabetes fulfil guideline recommended targets? A report from the EuroAspire III cross-sectional Study Group
Do capillary dried blood spot concentrations of gamma-hydroxybutyric acid mirror those in venous blood?: a comparative study
2015) DRUG TESTING AND ANALYSIS. 7(4). p.336-340 Mark(
EURObservational research programme: EUROASPIRE: the Euroaspire survey of cardiovascular prevention and diabetes in 24 countries in Europe
2015) EUROPEAN HEART JOURNAL. 36(16). p.950-951 Mark(
Prevalence and management of familial hypercholesterolaemia in coronary patients: an analysis of EUROASPIRE IV, a study of the European Society of Cardiology
2015) ATHEROSCLEROSIS. 241(1). p.169-175 Mark(
- Readiness for smoking cessation in coronary heart disease patients across Europe: results from the EuroAspire III survey
- Patients with coronary artery disease and diabetes need improved management: a report from the EUROASPIRE IV survey: a registry from the EuroObservational Research Programme of the European Society of Cardiology
- 2014
Assessing the validity of capillary dried blood spots used for gamma-hydroxybutyrate analysis from patients suspected of toxicity attending the emergency department
2014) CLINICAL TOXICOLOGY. 52(4). p.369-369 Mark(
The association between self-reported lifestyle changes and health-related quality of life in coronary patients: the EUROASPIRE III survey
2014) EUROPEAN JOURNAL OF PREVENTIVE CARDIOLOGY. 21(7). p.796-805 Mark(


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Friday's portion of St. Clair's annual Freedom Fest celebration is shaping up to be a fun-filled kickoff to the two-day event.
Freedom Fest, the city's annual Independence Day celebration, is scheduled for Friday and Saturday, June 21-22. All events will take place at Orchard Park.
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Skip to comments.Not a Big Fan of the Old Man, but Warming-Up to Rand Paul QUICK...
Posted on 02/13/2013 2:13:30 AM PST by Reaganite Republican
Any whod like to be added to the RR ping-list, pls FReepmail me at Reaganite Republican -TIA
I've been thinking that about Rand Paul myself! He's been good in Senate Committee hearings too.
I am VERY pleasantly surprised... very reasonable, principled, and politically skilled imho
Mr. Paul does not call for any cuts to entitlements in his speech.
Mr. Paul does not call for any cuts to Social Security in his speech.
Mr. Paul does not call for any cuts to Medicare in his speech.
Mr. Paul does not call for any cuts to Medicaid in his speech.
Mr. Paul is a nice man, but he is obviously not prepared to take on senior entitlement programs because he is afraid to say or do anything unpopular. He is no worse, but no better than all of the other Washington politicians who will not risk their cushy jobs to tackle our real problems.
So, what chance is there that there will be any cuts to entitlement programs (all of which are unconstitutional) when no one has the guts to call for cuts?
Also....RP basically endorsed Rubio's Amnesty plans.
Has anyone actually read what RP said? Are we just too busy cheerleading instead of standing up for our values?
Regarding specific cuts ... look to the Senator Paul's budget proposal.
It has been characterized as reducing "the average" SS benefit by 40 percent. What it does is preserve the earned benefits of those who paid in, not only by making SS solvent forever, but also by balancing the budget of the entity that "backs" SS.
It returns health insurance either to the private sector (for those who should pay for their own insurance) or to the states (for the poor).
It shuts down several departments of the federal government, returning their functions to the private-sector or to the states.
It lowers tax rates, closes loopholes, and otherwise simplifies the federal income tax structure.
Since we will all pay the same rate on income above the poverty level, we will have tax fairness among those of us of today; and, because the budget is balanced, we will have tax fairness between those of us of today and those who will succeed us.
Rand Paul has indicated a willingness to compromise, but compromise with whom? The other side doesn't have a starting point.
Clearly, we cannot pass Sen. Paul's budget this year. But, with the elections of 2014 and 2016, we may be able to pass something like it in the future, perhaps a compromise between it and Congressman Ryan's budget.
What Ryan and Rubio are lacking is fire in the belly. Without it, no Republican will win. I like Rand Paul and am hoping that he can start to raise his voice and go on the attack.
Agree completely. The only concern I have, which has been raised here, is that he's weak on immigration. I'm waiting to hear more.
But we have to unite behind a single candidate early.
Didn't watch any of the 3.
Did catch about one minute of Rubio. He looked like he was giving hand signals, left hand rubbed brow, right hand rubbed temple. Looked like he was swatting flies or something. He seemed nervous and flubbed some of his delivery. Later, I saw the thread of him reaching for the water bottle.
I remember the delivery criticism Jingal got a few years ago when he was the official responded. I expect the morning 'news' [a.k.a., propaganda] venues will be skewering Rubio this morning.
Rubio was 'hoping' Obama would take the Pubbies' budget advice. Amnesty Rubio wants to ensure 'securing the border' with a new law. [Either Rubio is naive or he is in on the ole shellgame — if 'securing the borders' is his first goal regarding illegals, that can be done with EXISTING laws. Wny should Obama take the pubbie budget advice? He won.]
CSPAN made reference to Paul's response and said they would show it later. It is probably online.
According to an early yahoo.com poll yesterday, some 76% of responders indicated they would not tune in The One's spiel. [I included myself in that group.]
He's the current front runner as far as my voting interests go for a 2016 Presidential candidate. Not even a close second at this point since I'm thinking Mark Levin isn't going to run.
Mr. Paul does not call for any cuts to entitlements in his speech.
Mr. Paul does not call for any cuts to Social Security in his speech.
Mr. Paul does not call for any cuts to Medicare in his speech.
Why don't you run for office on that plan, see how it goes.
He's the current front runner as far as my voting interests go for a 2016 Presidential candidate. Not even a close second at this point since I'm thinking Mark Levin isn't going to run.
The most you can hope for out of any talk show host is that they actually endorse someone during the primary season—other than that, look for more money-making books and iced tea.
What Ryan and Rubio are lacking is fire in the belly. Without it, no Republican will win. I like Rand Paul and am hoping that he can start to raise his voice and go on the attack.
Ryan and Rubio are just the latest in cookie cutter moderate Republicans, not altogether much different from Dole, Bush, McCain, Romney. Rand Paul is his father's son. And actually believes in the Constitution. Been a fan of the father for DECADES, and a fan of the son since I learned he lived here in Kentucky at least ten years ago. Flame away; I am accustomed to that on Free Republic.
That is a good suggestion, but I think it is easy for some people here to be a keyboard politician or run campaign from a keyboard to actually do something.
Listening to him in the run up to the last national election, I was wishing like he*& that HE'D be our nominee!
For the first time in history, men and women were guaranteed in America a chance to succeed based not on who your parents were, but on your own initiative, and desire to work. We're in danger, tho, of forgetting what made us great: the President seems to think the country can continue to borrow $50,000 every second... the President believes if we can just squeeze more money out of those that are working... I don't think it'll work.
The path we are on is not sustainable, but few in Congress -or in this Administration- seem to recongize that their actions are endangering the prosperity of this great nation...
Ronald Reagan said 'Government is not the answer to the problem, government is the problem': tonight, the President told the nation he disagrees- President Obama believes government is the solution, more taxes, more debt.
What the President fails to grasp is that the American system that rewards hard work is what made America so prosperous. What American needs is not Robin Hood, but Adam Smith: in the year we won our independence, Adam Smith described what creates the Wealth of Nations... he described a limited government that largely did not interfere with individuals in their pursuit of happiness.
All that we are -and all that we wish to be- is threatened by the notion that you can have 'something for nothing'... that you can have you cake and eat it too, that you can spend a TRILLION DOLLARS a year that you don't have...
Congress is debating the wrong things: every debate in Washington is about 'how much to increase spending' a little, or a lot- how much to increase taxes, a little, or a lot...
Few people understand that the sequester -it just slows the rate of growth. Even with the sequester -if it goes through- government will grow $7 TRILLION over the next decade... ONLY in Washington could an increase of $7T be called 'a cut'. Big Government is NOT your friend- Big Government gives you stuff- but keeps you poor.
Tonight I urge you to demand a new course: demand Washington change their ways, or they'll be sent home. We absolutely MUST pass a balanced budget amendment to the Constitution: the amendment must include strict spending and tax limitations. Liberals complain that the budget 'can't be balanced', but if we cut just ONE PENNY from each dollar we spend, the budget would be balanced in 6 or 7 years (!)
Video/more at Reaganite Republican
One penny?
I think the government spends about $3 trillion a year, half of it ~ $1.5T is borrowed(yearly deficit) To balance that it would have to cut that $1.5T in spending.
The sequester I thought cuts $100B billion this year (1/15 th of that yearly deficit), about half the cuts from defense, and you will hear screaming and wailing about that 1/15th assuming congress even lets it go.(its coming) In 18 months they couldnt find specific spending cuts to replace that $0.1T let alone $1.5.
(are these numbers accurate??)
Rubio called for the balanced budget last night too, the two should get together and produce a budget that is balanced. You know why they wont do that.
No amendment like that will ever be passed into law. But all hell would break loose if they even wrote a budget to do it.
"What Ryan and Rubio are lacking is fire in the belly"
Paul and other Republicans MUST learn to be more media-savvy, and that includes recognizing the obvious: that the MSM is not our friend.
Yesterday, before the SOTU, Paul went on CNN, with Candy Crowley.. 8 minute video here
Instead of discussing the important issues facing the country, and Obama's failed policies, Crowley attempted to draw Paul into a criticism of Rubio, and suggested that the GOP is fragmented. She then pivoted to the crucial question of will Mitch McConnell get primaried by a Tea Party candidate, and then, if Mitch manages to win his primary, can he beat Ashley Judd?
I mean, come on..oh please...Candy Crowley...Rand, are you kidding?..Remember, she's the one who went into the tank for Obama DURING the presidential debate.
I'm not picking on the good doctor. I like his policies, and what he stands for. But if we're gonna win, we have to get a lot smarter about it. First, why CNN? They have NO ratings. Who the hell watches that blimpette during the daytime anyways? Why not do it on FOX?..Cavuto would have been perfect.
And once she started asking him about a possible "schism" with Rubio, he should have just cut her off...something like, "Candy, are you serious? I came on the air with you to talk about the big problems that America faces, everything that Obama is doing wrong, and THIS is what you ask?"
Have we already forgotten how far in the tank the MSM was for Obama just a few months ago, how they have covered up Benghazi, and "Fast & Furious." ( when 's the last time you read anything about THAT?)
Wake up, GOP!!
Have we already forgotten how far in the tank the MSM is for Obama, how they have covered up Benghazi, and "Fast & Furious." (when's the last time you read anything about THAT?).
And howzabout the MSM covering up for O's point man on amnesty---Sen Menendez---who diddled little girls in the Dominican Republic---and harbored an illegal who was a registered sex offender in his office----whose arrest O's DOJ kiboshed to prevent a Menendez relection kerfluffle.
What about Bachmann? No?
Agreed with all, and we definitely need to know what we're dealing with in the MSM, BUT Fox is a problem too
They -and esp Hannity- are in bed with the Gee Oh Pee old guard, and allied in efforts directed AGAINST the TEA Party.
Fox, Boehner, McConnel, and Karl Rove have basically declared war on the TP, and Rand Paul has to take coverage where he can get it perhaps- might not be particularly welcome on Fox right now
Disclaimer: Opinions posted on Free Republic are those of the individual posters and do not necessarily represent the opinion of Free Republic or its management. All materials posted herein are protected by copyright law and the exemption for fair use of copyrighted works.


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LeBron James returned to Cleveland, Kevin Love joined him and suddenly the Cavaliers had the makings of the latest superteam.
SAN FRANCISCO (AP) - The message from Joe Torre shown on the video board at AT&T Park was clear and direct: "When in doubt, sit it out."
OAKLAND (AP) - Any time a team fires a coach after a 51-win season and back-to-back playoff appearances the message from ownership is clear: good is not good enough.
SANTA CLARA (AP) - Running back Marcus Lattimore is ready to return to the practice field at last, ready to forget the devastating knee injuries, surgeries and countless hours of rehab.
ALAMEDA (AP) - Every week there's a new problem and the same result for the Oakland Raiders.
ARLINGTON, Texas (AP) - Colt McCoy did it again. The small-town West Texas kid calmly led a winning drive at the home of the Dallas Cowboys.
KANSAS CITY, Mo. (AP) - A 2-foot-tall image of deer in multicolored neon with a bulls-eye on its tail is affixed to a wall in the Kansas City Royals locker room. It hangs between the stalls of Aaron Crow and Tim Collins, and has a "W'' underneath a crown.
KANSAS CITY, Mo. (AP) - Jake Peavy's son is eager for dad to bring home the World Series championship, and a cable car.
Mike Matheny needed some time to figure out what to say. Like the rest of the St. Louis Cardinals, the manager was leveled by the sudden death of Oscar Taveras.
OAKLAND (AP) - The Athletics have hired former Oakland and San Francisco first baseman and outfielder Mike Aldrete as bench coach on manager Bob Melvin's staff.
CLEVELAND (AP) - One of these games, the Raiders will put it all together.
SANTO DOMINGO, Dominican Republic (AP) - St. Louis Cardinals outfielder Oscar Taveras, a 22-year-old slugger who was regarded as one of the majors' top prospects, died Sunday in a car accident in his native Dominican Republic.
SAN FRANCISCO (AP) - With every pitch, Madison Bumgarner etched his place among the World Series greats.
SAN FRANCISCO (AP) - His throwing motion is weird, his swing is awkward, his tongue hangs out when he chases flyballs.
ST. SIMONS ISLAND, Ga. (AP) - Two items on Robert Streb's bucket list are attending an Oklahoma-Texas football game and playing at Augusta National.
Page 279 of 791
SANTA CLARA (AP) - Colin Kaepernick was convincing that he is a changed man and ready to stay put with the 49ers. A healthy man, too ...
CLEVELAND (AP) - Turns out, Stephen Curry has not entered some level of basketball infallibility.
PITTSBURGH (AP) - There's very little flash to Martin Jones. The San Jose Sharks goaltender speaks in a polite monotone, only too eager to deflect ...
PASADENA, Calif. (AP) - The last time Mexico faced Jamaica, it left the field as the champions of a major international tournament on U.S soil.
ORLANDO, Fla. (AP) - This was a 7-1 scoreline Brazil could enjoy.
OKLAHOMA CITY (AP) - After two losses to start the season, Oklahoma coach Patty Gasso wasn't sure about her team full of freshmen and sophomores.
ENGLEWOOD, Colo. (AP) - Super Bowl MVP Von Miller's camp has rejected a contract proposal that would have made him the highest-paid non-quarterback in NFL ...
SANTA CLARA (AP) - Despite being 27 years old, Torrey Smith qualifies as the elder statesman of the 49ers wide receiving group.
PARIS (AP) - Maria Sharapova was suspended Wednesday for two years for failing a drug test, labeled "the sole author of her own misfortune" because she ...
PITTSBURGH (AP) - Phil Kessel insists nothing has changed. Not his game. Not his attitude. Not the shape of his body or his commitment to winning.
MILWAUKEE (AP) - Jesse Hahn knew exactly why the Milwaukee Brewers beat him.
SAN FRANCISCO (AP) - One moment, Mac Williamson hit the go-ahead homer for his first career long ball as tens of thousands cheered him. The next ...
CLEVELAND (AP) - Stephen Curry's only basket in the first 30 minutes came off a broken play. He found himself in foul trouble again. His ...
CHICAGO (AP) - The fans stood and cheered when Clint Dempsey headed off the field in the second half, and the forward responded with his own ...
SAN FRANCISCO (AP) - What a game for Albert Suarez to draw for his home debut, in his second major league start no less.
Page 31 of 37
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Starts: December 05th, 2015 4:00 PM
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Maine Ave
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Join Events Online
The Lakeside Chamber of Commerce often has event postings that you can join and register for online!
Lakeside Chamber of Commerce's 17th Annual
Spirit of Christmas on Maine Ave.
Saturday, December 5th 2015 FREE to ATTEND!
Santa and his elves are hard at work getting ready for Christmas…
And the elves of the Lakeside Chamber of Commerce work to create an annual event that will attract and delight people of all ages.
There will be an atmosphere of an old-fashion hometown Christmas. The event features all the sights and sounds of Christmas;
• Local School performances
• Santa Claus – Photos with Santa
• Food and Drink
• Kid Activities
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• Booths - Crafters
• Lighting the Community Christmas Tree
Join us for some Holiday Fun!
To fill out Booth Application click here.
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Pumpkin Puffs
|Cooked pumpkin/Canned pumpkin
|2 Cup (32 tbs)
|1 Cup (16 tbs)
|Baking powder
|1 Teaspoon
|To Taste
|1 Tablespoon
|1 Tablespoon
1. Into a bowl mix the flour, baking powder, sugar and salt together.
2. Whisk the pumpkin and eggs and stir into the flour mixture.
3. In a high sided pan heat enough oil to come 1/3 of the way up.
4. Dropping teaspoons of batter in fry until golden.
5. Drain and sprinkle with sugar & cinnamon.
Recipe Summary
Rate It
Nutrition Rank
Nutrition Facts
Serving size
Calories 203 Calories from Fat 39
% Daily Value*
Total Fat 4 g6.8%
Saturated Fat 0.7 g3.5%
Trans Fat 0 g
Cholesterol 0 mg
Sodium 383.6 mg16%
Total Carbohydrates 37 g12.5%
Dietary Fiber 4.2 g16.8%
Sugars 3.8 g
Protein 5 g9.1%
Vitamin A Vitamin C
Calcium 9.7% Iron 8.8%
*Based on a 2000 Calorie diet


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This summer during the Hardin County Cattlemen's Association's chartered motor coach tour to Ohio, we were given the opportunity to hear a presentation by Stan Smith, a beef specialist with Ohio State University Extension. Stan is located in Fairfield County just east of Columbus and has conducted numerous demonstrations over the years and has done some cutting-edge work with grazing oats planted in late summer for fall and early winter grazing. He also edits a monthly beef cattle newsletter that is a team effort of the Ohio State University Beef Extension staff.
A local U.S. Army veteran said he retired from the military after God called him to run for public office.
Robert Lee Rosier, an Elizabethtown man who is running as a Republican, has filed a letter of intent with the Registry of Election Finance to challenge for the governor's seat in 2015.
Hardin County Clerk Kenny Tabb said candidates can file letters of intent early for the governor's race but cannot formally file for the office until after the general election in 2014.
A meeting scheduled next Tuesday in Henderson to take comment and provide information on Big Rivers Electric Corp.'s proposed rate increases has been canceled due to expected severe weather.
The state Public Service Commission said staff is trying to reschedule the session regarding the proposal.
The rate increase is estimated to increase monthly residential bills by about $25 to $30 per month to partially offset the loss of about $175 million in annual revenue after Century Aluminum smelter in Sebree ceases to be a Big Rivers customer at the end of
Question: Have the IRS' limits for 2014 Retirement Plans been released?
Answer: Many of the retirement plan annual limits are indexed for inflation. The IRS has just released the plan limits for 2014. Let's look at those limits in some detail below.
Contribution Limits: IRA contributions are unchanged at $5,500. Catch-up contributions remain at $1,000.
Plan deferral limits are unchanged at $17,500. Catch-up contributions remain at $5,500.
With the holiday shopping season about to go full swing, the Radcliff Small Business Alliance started a promotion to draw shopping dollars into member businesses.
The 5 for 5 promotion is meant to encourage shoppers to spend $5 in five RSBA member businesses for a chance to win $500. Cards used to keep track of the purchases can be picked up at any participating alliance member, board member John Flanagan said.
Flanagan said the idea originated from two RSBA members, Tamara Ohler and Pam Ogden-Crum, as a way to get customers into member's stores.
As harvest concludes, many Hardin County farmers already have begun planning for 2014. A major item on the planning list is variety selection for the 2014 corn crop. Variety can be one of the most crucial factors in determining yield and careful thought should be put in to determining what seed to plant on what acre.
The largest local corn variety trial in the state is the University of Kentucky's. This year, varieties from 15 companies who market seed corn in the state, are compared at five different test sites.
Question: I get all stressed out when I face Christmas shopping and debt from Christmas gift purchases. Is there a way I can have the money I need when I need it without going into debt?
Answer: Many people have these same feelings this time of year. There is not an instant formula which will help you short term, but there are longer term behavior changes that will solve your problem. See the 10 commandments of personal finance below. Now is the time to resolve to change your habits for financial success.
By Leanna Milby
Question: Every year, I promise myself the same thing, to be more financially responsible during the holiday season. Please share some (realistic) pointers to make this the year I actually do it.
Question: What is a "paid-up" status with my life insurance policy?
Answer: You might still be making payments on your life insurance policy despite the fact that its cash value is sufficient to maintain your coverage. In that case, you may have better use for the money you're paying as premiums. Find out now if you've achieved a paid-up status.
The News-Enterprise
The Hardin County Chamber of Commerce announced the hiring of a new relationship manager. Heather Heuman is joining the chamber team to enhance the chamber's ongoing support to local businesses.
"We want to make sure our members are getting the most out of their chamber membership," said Brad Richardson, Chamber president and CEO. "That's what Heather will be helping them do every day."
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The News-Enterprise is your source for local news, sports, events and information in Elizabethtown, KY, Hardin County and the surrounding area.